N-substituted-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine and related compounds as analgesic and hypotensive agents

ABSTRACT

There are disclosed compounds having the formula ##STR1## wherein R 1  is hydrogen or loweralkyl; R 2  is loweralkyl, arylloweralkyl, diarylloweralkyl or --CH 2  CHOHCH 2  OR 5 , R 5  being aryl, or alternatively --NR 1  R 2  taken together is ##STR2## R 6  being aryl, arylloweralkyl, diarylloweralkyl, ##STR3## and R 3  and R 4  are each independently methoxy or hydroxy, which compounds are useful as analgesic and hypotensive agents.

This invention relates to compounds having formula I below ##STR4##where R₁ is hydrogen or loweralkyl; R₂ is loweralkyl, arylloweralkyl,diarylloweralkyl or --CH₂ CHOHCH₂ OR₅, R₅ being aryl, or alternatively--NR₁ R₂ taken together is ##STR5## R₆ being aryl, arylloweralkyl,diarylloweralkyl, ##STR6## and R₃ and R₄ are each independently methoxyor hydroxy, which compounds are useful as analgesic and hypotensiveagents; to pharmaceutical compositions comprising an effective amount ofsuch a compound; to a method of alleviating pain which comprisesadministration of an effective amount of such a compound and to a methodof reducing blood pressure which comprises administration of aneffective amount of such a compound.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, optical and geometricalisomers thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following general rules of terminology shall apply throughout thespecification and the appended claims.

Unless otherwise stated or indicated the term loweralkyl denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy.

Unless otherwise stated or indicated, the term loweralkoxy denotes astraight or branched alkoxy group having from 1 to 6 carbon atoms.Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy.

Unless otherwise stated or indicated, the term halogen shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term aryl shall mean a phenylgroup having 0, 1, 2 or 3 substituents each of which being independentlyhydroxy, nitro, loweralkyl, loweralkoxy, halogen or CF₃.

The compounds of formula I are prepared by utilizing one or more of thereaction steps described below. Throughout the description of thesynthetic steps, the definitions of R₁ through R₆ are as given aboveunless otherwise stated or indicated.

STEP A

The chloro compound of formula II is reacted with an amine of theformula III to obtain a compound of formula Ia. ##STR7##

This reaction is typically conducted in the presence of milled K₂ CO₃(acid scavenger) and KI (catalyst) as well as a suitable solvent(including polar solvent) such as anhydrous dimethylformamide andstirring the reaction mixture at a temperature of about 50° to 100° C.

Where the group R₁ is loweralkyl in the above reaction step, the amineof formula III is prepared from the secondary amine R₂ --NH₂ andloweralkyl chloride R₁ --Cl in a routine manner known to the art.

STEP B

A compound of formula I where one or both of R₃ and R₄ are hydroxy isprepared by reacting compound Ia with pyridine hydrochloride in aroutine manner known to the art. ##STR8##

STEP C

For introducing a substituent --CH₂ CHOHCH₂ OR₅ onto the amino nitrogen,the following scheme is used.

First, compound II is converted to the compound of formula IV in aroutine manner known to the art (Gabriel synthesis). ##STR9##

Secondly, compound IV is reacted with an epoxy compound of formula V ina routine manner known to the art to afford a compound of formula VI.##STR10##

Alternatively to the above, compound IV may be reacted withchloromethyloxirane in a routine manner known to the art to obtain thecompound of formula VII and the latter reacted with an aryloxy anion offormula VIII in a routine manner known to the art to obtain compound VI.##STR11##

STEP D

The secondary amine hydrogen of compound VI can be replaced with aloweralkyl group R₁ in a routine manner known to the art to afford acompound of formula IX. ##STR12##

STEP E

One or both of the methoxy groups in compound IX can be converted tohydroxy groups in substantially the same manner as described in STEP B.##STR13## (where R₃ or R₄ or both are hydroxy)

STEP F

Where the group --NR₁ R₂ has the formula, ##STR14## it is convenient toreact piperazine with compound II at 1:2 stoichiometric ratio to obtaina compound formula X. ##STR15##

Compounds of this invention having formula I are useful as analgesicagents due to their ability to alleviate pain in mammals. The activityof the compounds is demonstrated in the2-phenyl-1,4-benzoquinone-induced writhing test in mice, a standardassay for analgesia [Proc. Soc. Exptl. Biol. Med. 15, 729 (1957)]. Table1 shows test results for some of the compounds of this invention.

                  TABLE 1                                                         ______________________________________                                        Analgesic Activity                                                            (Phenylquinone Writhing)                                                      Compound                ED.sub.50 mg/kg, s.c.                                 ______________________________________                                        N-methyl-N-(2-phenylethyl)-5,6-dimethoxy-                                                             13.6                                                  1,2-benzisoxazole-3-propanamine                                               N-[2-(4-fluorophenyl)ethyl]-5,6-dimethoxy-                                                            3.8                                                   1,2-benzisoxazole-3-propanamine                                               3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-                                                             1.7                                                   propyl]-5,6-dimethoxy-1,2-benzisoxazole                                       pentazocine (reference compound)                                                                      1.3                                                   ______________________________________                                    

Compounds of the present invention are also useful as antihypertensiveagents due to their ability to depress blood pressure in mammals.Antihypertensive activity is measured in the spontaneous hypertensiverat by the indirect tail cuff method described in "Methods inPharmacology", A. Schwartz, Ed., Vol. I, Appleton-Century Crofts, NewYork, N.Y., 1971, p. 135. In this procedure a group of five animals aretreated orally for three days with the test compound in relation to acontrol group of the same number. The drop in blood pressure is measuredon the third day following administration. The antihypertensiveactivities of some of the compounds, expressed as a decrease in meanarterial blood pressure (in mm Hg), are given in Table 2.

                  TABLE 2                                                         ______________________________________                                        Antihypertensive Activity                                                                           Pressure                                                                      Drop (mmHg)                                             Compound              at 50 mg/kg, p.o.                                       ______________________________________                                        N-(2-phenylethyl)-5,6-dimethoxy-1,2-                                                                32                                                      benzisoxazole-3-propanamine                                                   3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-                                                           68                                                      propyl]-5,6-dimethoxy-1,2-benzisoxazole                                       Diltiazem (reference compound)                                                                      39                                                      ______________________________________                                    

Antihypertensive activities of the compounds of this invention can alsobe ascertained with reference to α₁ -adrenergic receptor antagonistactivity as determined according to the method of Peroutka, et al.,Neuropharmacology, 16, 549 (1977). The procedure used in this inventionis described below.

[³ H]-WB4101: α₁ -ADRENERGIC RECEPTOR BINDING IN RAT BRAIN

This in vitro [³ H]-WB4101 receptor binding assay quantitates theprimary blood pressure lowering effects through α₁ -receptor blockade.WB-4101 (2-(2,6-dimethoxyphenoxyethyl)aminoethyl-1,4-benzodioxane) is aspecific and potent antagonist of the α₁ -adrenoceptor characterized invitro in rat brain, heart, vascular smooth muscle and gastrointestinalsmooth muscle. Peroutka et al. (1977) demonstrated a good correlationbetween the inhibition of ³ H-WB4101 binding in brain membranepreparations and the blockade of peripheral vascular effects ofnorepinephrine. WB4101 labels an antagonist binding site on the α₁-adrenoceptor, since it is preferentially displaced by antagonists whileα-noradrenergic agonists preferentially displace the ³ H-agonists

PROCEDURE

This Assay method is adapted from the Peroutka article mentioned above.

Reagents

1. 0.5M Tris Buffer, pH 7.7

a. 57.2 g Tris HCl 16.2 g Tris base q.s. to 1 liter (0.5M Tris buffer,pH 7.7 at 25° C.).

b. Make a 1:10 dilution in distilled H₂ O (0.05M Tris Buffer, pH 7.7)

2. [Phenoxy-3-³ H(N)]-WB4101,(2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane, (20-25Ci/mmol) is obtained from New England Nuclear.

For IC₅₀ determination: ³ H-WB4101 is made up to a concentration of 20nM and 50 micro liter is added to each tube (yields a finalconcentration of 0.5 nM in the 2 ml assay volume).

3. L-norepinephrine bitartrate is obtained from Sigma Chemical Co.

A 10 mM stock solution of norepinephrine is made up in 0.01N HCl and 20micro liter added to three tubes to determine nonspecific binding. Thisyields a final concentration of 100 micro liter in the assay.

4. Test Compounds

For most assays, a 1 mM stock solution is made up in a suitable solventand serially diluted, such that the final concentration in the assayranges from 10⁻⁵ to 10⁻⁸ M. Seven concentrations are usually used foreach assay. Higher or lower concentrations may be used, depending on thepotency of the drug.

B. Tissue Preparation

Male Wistar rats (100-150 g) are killed by decapitation and their brainsrapidly removed. Whole brains minus cerebella are homogenized in 50volumes of ice-cooled 50 mM Tris buffer (pH 7.7 at 25° C.) using aTekmar homogenizer. The homogenate is centrifuged at 40,000 g, thesupernatant discarded and the pellet resuspended in fresh 50 mM Trisbuffer and recentrifuged at 40,000 g. The final pellet is resuspended inthe original volume of fresh 50 mM Tris buffer, pH 7.7. The final tissueconcentration in the assay is 10 mg/ml. Specific binding isapproximately 9% of the total added ligand and approximately 80% of thetotal bound ligand.

C. Assay

    ______________________________________                                        100    micro liter                                                                              0.05M Tris buffer, pH 7.7                                   830    micro liter                                                                              H.sub.2 O                                                   20     micro liter                                                                              Vehicle (for total binding) or 10 mM                                          L-NE (for nonspecific binding) or                                             appropriate drug concentrations                             50     micro liter                                                                              .sup.3 H-WB4101 stock solution                              1000   micro liter                                                                              Tissue suspension                                           ______________________________________                                    

Sample tubes are kept on ice for additions, then vortexed and incubatedfor 15 minutes at 15° C. The binding is terminated by rapid vacuumfiltration through Whatman GF/B filters, followed by three 5 ml washeswith ice-cold 0.05M Tris buffer. The filters are counted in 10 ml ofliquid scintillation cocktail. Specific WB 4101 binding is defined asthe difference between the total binding and that bound in the presenceof 100 micro molar NE. IC₅₀ calculations are performed using computerderived log-probit analysis.

Test results for some of the compounds of this invention are presentedin Table 3.

                  TABLE 3                                                         ______________________________________                                        α.sub.1 -adrenergic receptor antagonist activity (IC.sub.50)                              [.sup.3 H]-WB4101: α.sub.1 -Adrenergic                                  Receptor (IC.sub.50) Antagonist                             Compound          Activity                                                    ______________________________________                                        N-(2-phenylethyl)-5,6-dimethoxy-                                                                8.3 × 10.sup.-8 M                                     1,2-benzisoxazole-3-propanamine                                               N-methyl-N-(2-phenylethyl)-5,6-                                                                 6.7 × 10.sup.-8 M                                     dimethoxy-1,2-benzisoxazole-3-                                                propanamine                                                                   phenoxybenzamine (reference                                                                     1.2 × 10.sup.-8 M                                     compound) Prazocin (reference compound)                                                          8.0 × 10.sup.-10 M                                   ______________________________________                                    

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteralpreparations can be enclosed in disposable syringes or multiple dosevials made of glass or plastic.

Examples of the compounds of this invention include:

N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-[(2,4-dimethoxy)phenylmethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-methyl-N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-[2-(4-fluorophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-[2-(4-nitrophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-[2-(3,4-dimethoxyphenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-methyl-N-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-6-hydroxy-5-methoxy-1,2-benzisoxazole-3-propanamine;

N-[3-(diphenyl)propyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

N-[(2-hydroxy-3-phenoxy)propyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine;

3-[3-[4-[2-oxobenzimidazol-1-yl]-1-piperidinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole;

3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole;

3-[3-(4-diphenylmethyl-1-piperazinyl)propyl]-5,6-dimethoxy-1,2-benzisoxazole;

3-[3-[4-(2,3,4-trimethoxyphenyl)-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole;

3-[3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole;

3-[3-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]propy]-5,6-dimethoxy-1,2-benzisoxazole;

3-[3-[4-[4-[bis(4-fluorophenyl)butyl]]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole;

3-[3-[4-[3-[6-fluoro-1,2-benzisoxazol-3-yl]propyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole;and

3-[3-[4-[3-[5,6-dimethoxy-1,2-benzisoxazol-3-yl]propyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole.

The following examples are presented in order to illustrate thisinvention.

EXAMPLE 1 N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanaminehydrochloride

To 75 ml of dry dimethylformamide (DMF) were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.0 g), benzylamine(4.5 ml), milled potassium carbonate (10 g) and potassium iodide (0.01g).

After five hours of stirring at 80° C., the mixture was poured into 500ml of water, stirred for five minutes and then extracted with ethylacetate. The organic layer was washed with water (2X) and thereafterdried (saturated sodium chloride, anhydrous magnesium sulfate).

After filtration, the solvent was evaporated, leaving about 10 g of oilwhich was eluted on a silica gel column with 5% methanol/dichloromethane(DCM) via high performance liquid chromatography (HPLC). The desiredfractions were combined and concentrated to about 4 g of oil.

This oil was dissolved in ether, the pH adjusted to 1 with etheral-HCl,and the resultant precipitate collected and dried, 3.2 g, d @240° C.This material was recrystallized from isopropanol/ether (1:10) to yield2.3 g of crystals, d @240° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.19 H.sub.22 N.sub.2 O.HCl:                                                 62.89% C 6.39% H  7.72% N                                   Found:            62.75% C 6.36% H  7.63% N                                   ______________________________________                                    

EXAMPLE 2N-[(2,4-dimethoxy)phenylmethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanaminehydrochloride

To 90 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.1 g),2,4-dimethoxybenzylamine hydrochloride (8.1 g), milled potassiumcarbonate (20 g) and potassium iodide (0.01 g).

After six hours of stirring at 90° C., the mixture was poured into 500ml of water, stirred for five minutes and then extracted with ethylacetate/ether. The organic layer was washed with water (2×100 ml) andsaturated sodium chloride solution (1×100 ml), and then dried overanhydrous magnesium sulfate.

After filtration, the solvents were evaporated, leaving about 10 g ofoil which was eluted on a silica gel column with 5% methanol/DCM viaHPLC. The desired fractions were combined, concentrated to 4 g of oil,dissolved in ether and then acifidied to pH 1 with ethereal-HCl. Theresultant precipitate was collected and dried to yield 3.0 g, d @210° C.This material was recrystallized from methanol/ether (1:5) to yield 2.5g of solid, d @214° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.21 H.sub.26 N.sub.2 O.sub.5.HCl:                                           59.46% C 6.44% H  6.63% N                                   Found:            59.53% C 6.37% H  6.54% N                                   ______________________________________                                    

EXAMPLE 3N-methyl-N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamineoxalate

To 75 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.1 g),N-benzylmethylamine (2.4 ml), milled K₂ CO₃ (10 g) and KI (0.01 g).

After seven hours of stirring at 90° C., the mixture was poured into 200ml of water, stirred for five minutes and then extracted withether/ethyl acetate. The organic layer was washed with water (2X) andsaturated NaCl, and then dried over anhydrous magnesium sulfate.

After filtration, the solvents were evaporated, leaving about 10 g ofoil, which was eluted on a silica gel column with 5% methanol/DCM viaHPLC. The desired fraction was collected, concentrated to about 5 g ofoil, dissolved in ether, and then acidified to pH 1 with ethereal oxalicacid.

The resultant precipitate was collected and dried to yield 2.6 g ofsolid, d @110° C. This material was recrystallized from isopropanol toyield 2.3 g of crystals, d @132° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.20 H.sub.24 N.sub.2 O.sub.3.C.sub.2 H.sub.2 O.sub.4      :              61.38% C  6.09% H  6.51% N                                     Found:         61.49% C  6.18% H  6.47% N                                     ______________________________________                                    

EXAMPLE 4N-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanaminehydrochloride

To 100 ml of dry DMF were added 3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g), 2-(phenyl)ethylamine (6.05 g), milled K₂ CO₃g) and KI (0.01 g)

After six hours of stirring at 90° C., the mixture was poured into 500ml of water, stirred for five minutes and then extracted withether/ethyl acetate. The organic layer was washed with water (2×100 ml)and saturated NaCl (1×100 ml), and then dried over anhydrous MgSO₄.

After filtration, the solvents were evaporated, leaving about 12 g ofoil which was eluted on a silica gel column with 5% methanol/DCM viaHPLC. The desired fractions were combined and concentrated to 4.3 g ofoil.

This oil was dissolved in ether, the pH of the solution adjusted to 1with ethereal-HCl, and the resultant precipitate collected and dried toyield 3.4 g, d @220° C. This material was recrystallized frommethanol/ether (1:1) to yield 3.0 g of crystals, d @227° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.20 H.sub.24 N.sub.2 O.sub.3.HCl:                                           63.73% C 6.69% H  7.43% N                                   Found:            63.55% C 6.70% H  7.34% N                                   ______________________________________                                    

EXAMPLE 5N-[2-(4-fluorophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanaminehydrochloride

To 100 ml of dry DMF were added 2-(4-fluorophenyl)ethylaminehydrochloride (10 g) and milled K₂ CO₃ (20 g). After five minutes ofstirring, 3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g) andKI (0.01 g) were added.

After fourteen hours of stirring at 90° C., the mixture was filtered andthe filtrate was concentrated to a dark oil, stirred with water and thenextracted with ether. The ether solution was washed with water (2X) andthen dried (saturated NaCl, anhydrous MgSO₄).

After filtration, the solvent was evaporated, leaving about 11 g of oil,which was eluted on a silica gel column with 5% methanol/DCM. Thedesired fractions were combined and concentrated to 3.8 g of oil whichwas dissolved in ether, the pH was adjusted to 1 with etheral-HCl, andthe resultant precipitate collected and dried to give 3.5 g, d @210° C.This material was recrystallized twice from methanol/ether (1:2) to give2.3 g of crystals, d @228° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for                                                                              60.83% C   6.13% H  7.10% N                                     C.sub.20 H.sub.23 FN.sub.2 O.sub.3.HCl:                                       Found:        60.79% C   6.44% H  7.00% N                                     ______________________________________                                    

EXAMPLE 6N-[2-(4-nitrophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanaminehydrochloride

To 100 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g),(4-nitrophenyl)ethylamine hydrochloride (10 g), milled K₂ CO₃ (20 g) andKI (0.01 g).

After twelve hours of stirring at 90° C., the mixture was poured into500 ml of water and then extracted with ethyl acetate. The organic layerwas washed with water (2×) and then dried (saturated NaCl, anhydrousMgSO₄).

After filtration, the solvent was evaporated, leaving about 16 g of oil,which was eluted on a silica gel column with 4% methanol/DCM via HPLC.The desired fractions were combined and concentrated to 3.0 g of oil,which solidified on standing, m.p. 96° C.

This material was dissolved in ether, pH adjusted to 1 with etheral-HCl,and the resultant precipitate collected and dried to yield 2.5 g, d@175° C. This was recrystallized from methanol/ether (1:2) to give 2.0 gof solid, d @188° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for                                                                             56.94% C  5.73% H   9.96% N                                      C.sub.20 H.sub.23 N.sub.3 O.sub.5.HCl:                                        Found:       56.90% C  5.61% H  10.01% N                                      ______________________________________                                    

EXAMPLE 7N-[2-(3,4-dimethoxyphenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamineoxalate

To 100 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazoIe (5.1 g),2-(3,4-dimethoxyphenyl)ethylamine (7.2 g), milled K₂ CO₃ (20 g) and KI(0.01 g).

After six hours of stirring at 80° C., the mixture was poured into 500ml of water, stirred for five minutes and then extracted with ethylacetate/ether. The organic layer was washed with water (2×100 ml) andsaturated NaCl (1×100 ml), and then dried over anhydrous MgSO₄.

After filtration, the solvents were evaporated, leaving 8 g of oil whichwas eluted on a silica gel column with 8% methanol/DCM via HPLC. Thedesired fractions were combined and concentrated to 3 g of oil, whichwas dissolved in ether/ethyl acetete and acidified to pH 1 with etherealoxalic acid. The resultant precipitate was collected and dried to yield3.0 g, d @192° C. This material was recrystallized from methanol toyield 2.8 g, d @196°-7° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for 58.76% C  6.17% H  5.71% N                                     C.sub.22 H.sub.28 N.sub.2 O.sub.5.C.sub.2 H.sub.2 O.sub.4 :                   Found:         58.77% C  6.18% H  5.63% N                                     ______________________________________                                    

EXAMPLE 8N-methyl-N-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamineoxalate

To 75 ml of DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (4.0 g),N-methylphenylethylamine (2.0 g), milled K₂ CO₃ (5.0 g) and KI (0.01 g).

After six hours of stirring at 90° C. and twenty hours at ambienttemperature, the mixture was poured into 300 ml of water, stirred forfive minutes, and then extracted with ethyl acetate/ether. The organiclayer was washed with water (2X), and then dried (saturated NaCl,anhydrous MgSO₄).

After filtration, the solvents were evaporated, leaving about 5 g ofoil, which was eluted on a silica gel column with ethyl acetate viaHPLC. The desired fraction was collected and concentrated to 2.6 g ofoil. This oil was dissolved in ether and acidified to pH 1 withethereal-oxalic acid. The resultant precipitate was collected and driedto yield 2.8 g, d @157° C. This material was recrystallized fromisopropanol/ether (1:10) to yield 2.2 g of solid, d @157° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for 62.15% C  6.35% H  6.30% N                                     C.sub.21 H.sub.26 N.sub.2 O.sub.3.(CO.sub.2 H).sub.2 :                        Found:         62.40% C  6.40% H  6.32% N                                     ______________________________________                                    

EXAMPLE 9N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3-propanamineoxalate

To 50 ml of DMF were added 3-(3-chloro-5,6-dimethoxy-1,2-benzisoxazole(5.0 g), N-[2-(3,4-dimethoxyphenethyl)]-N-methylamine (3.4 g), milled K₂CO₃ (4.0 g) and KI (0.01 g).

After five hours of stirring at 80° C., the mixture was poured into 500ml of water, stirred for five minutes and then extracted with ethylacetate. The organic layer was collected, washed with water (2X) anddried (saturated NaCl, anhydrous MgSO₄).

After filtration, the solvent was evaporated, leaving 8 g of oil, whichwas purified via HPLC on silica gel using 3% methanol/DCM as the elutingsolvent. The desired fraction was collected and concentrated to 5 g ofoil. This oil was dissolved in ether, the pH adjusted to 1 withethereal-oxalic acid, and the resultant precipitate collected and driedto yield 4.0 g, d @146° C. This material was recrystallized fromdichloromethane/ether (1:1) to yield crystals, d @146° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for 59.51% C  6.39% H  5.55% N                                     C.sub.23 H.sub.30 N.sub.2 O.sub.5.(CO.sub.2 H).sub.2 :                        Found:         59.33% C  6.28% H  5.55% N                                     ______________________________________                                    

EXAMPLE 10N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-6-hydroxy-5-methoxy-1,2-benzisoxazole-3-propanamine

To 70 ml of dry DMF were added3-(3-chloropropyl)-6-hydroxy-5-methoxy-1,2-benzisoxazole (4.4 g),N-[2-(3,4-dimethoxyphenethyl)]-methylamine (3.0 g), NaHCO₃ (10 g) and KI(0.01 g).

After four hours of stirring at 90° C., the mixture was poured into 200ml of water, stirred for five minutes and then extracted with ethylacetate. The ethyl acetate layer was washed with water (2×100 ml) andsaturated NaCl (1×100 ml), and then dried over anhydrous MgSO₄.

After filtration, the solvent was evaporated, leaving about 8 g of oil,which was eluted on a silica gel column with 10% methanol/DCM via HPLC.The desired fraction was concentrated to a brown oil, which solidifiedto 4 g of solid, m.p. 98°-100° C. This material was recrystallized twicefrom isopropyl ether/methanol (10:1) to yield 2.5 g of solid, m.p.112°-3° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.22 H.sub.28 N.sub.2 O.sub.5 :                                            65.98% C   7.05% H  7.00% N                                   Found:          65.56% C   7.06% H  6.86% N                                   ______________________________________                                    

EXAMPLE 11N-[3-(diphenyl)propyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3-propanamineoxalate

To 100 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.0 g),N-methyl-3,3-diphenylpropylamine (5.6 g), milled K₂ CO₃ (10 g), and KI(0.01 g).

After seven hours of stirring at 90° C., the mixture was poured into 500ml of water, stirred for five minutes and then extracted withether/ethyl acetate. The organic layer was washed with water (2X) anddried (saturated NaCl, anhydrous MgSO₄).

After filtration, the solvents were evaporated, leaving about 11 g ofoil, which was eluted on a silica gel column with ethyl acetate viaHPLC. The desired fraction was concentrated to about 4 g of oil, whichwas dissolved in ether, and acifidied to pH 1 with ethereal-oxalic acid.The resultant precipitate was collected, washed with ether, and thendried to yield 3.8 g, d @65° C. This material was recrystallized fromisopropanol/ether (1:5) to give 3.0 g of crystals, d @137° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for 65.86% C  6.71% H  5.49% N                                     C.sub.28 H.sub.32 N.sub.2 O.sub.3.C.sub.2 H.sub.2 O.sub.4 :                   Found:         65.97% C  6.59% H  5.02% N                                     ______________________________________                                    

EXAMPLE 12N-[(2-hydroxy-3-phenoxy)propyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamineoxalate

To 75 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (3.8 g),2-hydroxy-3-phenoxypropylamine (5.0 g), milled K₂ CO₃ (10 g) and KI(0.01 g).

After seven hours of stirring at 90° C., the mixture was poured into 200ml of water, stirred for five minutes and then extracted with ethylacetate. The organic layer was washed with water (2X) and saturatedNaCl, and then dried over anhydrous MgSO₄.

After filtration, the solvent was evaporated, leaving about 7 g of oil,which was eluted on a silica gel column with 8% methanol/DCM via HPLC.The desired fractions were combined and concentrated to about 3 g ofoil, which was dissolved in ether and then acidified to pH 1 withethereal-oxalic acid. The resultant precipitate was collected and driedto yield 3.0 g (d @135° C.). This material was recrystallized twice fromisopropanol/methanol (1:1) to yield 2.3 g of solid, d @180° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for 57.97% C  5.92% H  5.88% N                                     C.sub.21 H.sub.26 N.sub.2 O.sub.5.C.sub.2 H.sub.2 O.sub.4 :                   Found:         58.53% C  5.93% H  6.00% N                                     ______________________________________                                    

EXAMPLE 133-[3-[4-[2-oxobenzimidazol-3-yl]-1-piperidnyl]propyl]-5,6-dimethoxy-1,2-benzisoxazolehydrochloride

To 80 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.0 g),4-(2-oxo-1-benzimidazol-1-yl)piperidine (4.3 g), milled K₂ CO₃ (10 g)and KI (0.01 g).

After four hours of stirring at 85° C., the mixture was poured into 200ml of water, stirred for five minutes and then extracted with ethylacetate. The organic layer was washed with water (2X) and dried(saturated NaCl, anhydrous MgSO₄).

After filtration, the solvents were evaporated, leaving 10 g of solidwhich was eluted on a silica gel column with 5% methanol/DCM via HPLC.The desired fractions were combined and concentrated to 5 g of solid,which was dissolved in warm isopropanol and acidified to pH 1 withetheral-HCl. The mixture was cooled and diluted with ether, whereupon asolid precipitated, which was collected and dried to give 6.0 g, m.p.˜255° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.24 H.sub.28 N.sub.4 O.sub.4.HCl:                                      60.94% C   6.18% H  11.85% N                                     Found:       60.61% C   6.21% H  11.74% N                                     ______________________________________                                    

EXAMPLE 143-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole

To 80 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g),4-(2-methoxyphenyl)piperazine (3.8 g), milled K₂ CO₃ (10 g) and KI (0.1g).

After three hours of stirring at 85° C., the mixture was poured into 200ml of water and extracted with ethyl acetate. The organic layer waswashed with water (2X) and dried (saturated NaCl, anhydrous MgSO₄).

After filtration, the solvent was evaporated, leaving about 8 g of oil,which was eluted on a silica gel column with 3% methanol/DCM via HPLC.The desired fractions were combined and concentrated to an oil, whichwas dissolved in ether, the pH adjusted to 1 with ethereal-HCl, and theresultant precipitate collected and dried to give 2.7 g, d @220° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.23 H.sub.29 N.sub.3 O.sub.4.HCl:                                           61.67% C 6.75% H  9.38% N                                   Found:            61.49% C 6.61% H  9.24% N                                   ______________________________________                                    

EXAMPLE 153-[3-(4-diphenylmethyl-1-piperazinyl)propyl]-5,6-dimethoxy-1,2-benzisoxazoleoxalate

To 75 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (3.5 g),1-(diphenylmethyl)piperazine (3.5 g), milled K₂ CO₃ (10 g) and KI (0.01g).

After six hours of stirring at 90° C., the mixture was poured into 500ml water, stirred for five minutes and then extracted with ethylacetate. The ethyl acetate layer was washed with water (2X) and dried(saturated NaCl, anhydrous MgSO₄).

After filtration, the solvent was evaporated, leaving about 7 g of oilwhich was eluted on a silica gel column with ethyl acetate via HPLC. Thedesired fraction was concentrated to about 4 g of oil which wasdissolved in ethyl ether and the pH adjusted to 1 with ethereal oxalicacid. The resultant precipitate was collected and dried to yield 4.0 g,d @115° C. This material was recrystallized twice fromisopropanol/methanol (1:1) to yield 2.7 g, d @228° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for 66.29% C  6.28% H  7.48% N                                     C.sub.29 H.sub.33 N.sub.3 O.sub.3.C.sub.2 H.sub.2 O.sub.4                     Found:         66.13% C  6.43% H  7.40% N                                     ______________________________________                                    

EXAMPLE 163-[3-[4-(2,3,4-trimethoxyphenyl)-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazoleoxalate

To 75 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (3.5 g),N-(2,3,4-trimethoxybenzyl)piperazine (3.5 g), milled K₂ CO₃ (10 g) andKI (0.01 g).

After seven hours of stirring at 90° C., the mixture was poured into 300ml of water, stirred for five minutes and then extracted with ethylacetate. The ethyl acetate layer was washed with water (2X) and dried(saturated NaCl, anhydrous MgSO₄).

After filtration, the solvent was evaporated, leaving about 6.5 g of oilwhich was eluted on a silica gel column with 1% methanol/ethyl acetatevia HPLC. The desired fraction was concentrated to 5.0 g of oil whichwas dissolved in ethyl ether and the solution acidified to pH 1 withethereal oxalic acid. The resultant precipitate was collected and driedto yield 5.1 g, d @237° C. This material was recrystallized twice fromisopropanol/methanol (1:1) to yield 3.5 g of crystals, d @237° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for 54.13% C  5.91% H  6.31% N                                     C.sub.26 H.sub.35 N.sub.3 O.sub.6.2C.sub.2 H.sub.2 O.sub.4                    Found:         53.85% C  6.12% H  6.21% N                                     ______________________________________                                    

EXAMPLE 173-[3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole

To 75 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (4.1 g),1-[bis(4-fluorophenyl)methyl]piperazine (4.3 g), milled K₂ CO₃ (10 g)and KI (0.01 g).

After six hours of stirring at 90° C., the mixture was poured into 300ml of water, stirred for five minutes and then extracted withether/ethyl acetate. The organic layer was washed with water (2X) anddried (saturated NaCl, anhydrous MgSO₄).

After filtration, the solvents were evaporated, leaving about 9 g of oilwhich was eluted on a silica gel column with ethyl acetate via HPLC. Thedesired fraction was concentrated to 2.8 g of solid, m.p. 163°-8° C.This material was recrystallized twice from isopropyl ether/methanol(3:1) to yield 2.1 g, m.p. 173°-5° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.29 H.sub.31 F.sub.2 N.sub.3 O.sub.3                                      68.26% C  6.16% H  8.28% N                                    Found:          68.95% C  6.13% H  8.33% N                                    ______________________________________                                    

EXAMPLE 183-[3-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazoleoxalate

To 75 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (5.12 g),1-[(4-chlorophenyl)phenylmethyl]-piperazine (5.0 g), milled K₂ CO₃ (10g) and KI (0.01 g).

After six hours of stirring at 90° C., the mixture was poured into 500ml of water, stirred for five minutes and then extracted with ethylacetate. The ethyl acetate layer was washed with water (2X) and dried(saturated NaCl, anhydrous MgSO₄).

After filtration, the solvent was evaporated, leaving about 8 g of oilwhich was eluted on a silica gel column with ethyl acetate via HPLC. Thedesired fraction was collected, concentrated to 4.5 g of oil, thendissolved in ether, the pH of the solution adjusted to 1 with etheraloxalic acid, and the resultant precipitate collected and dried to yield4.3 g, d @115° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for  62.46% C  5.75% H  7.05% N                                    C.sub.29 H.sub.32 ClN.sub.3 O.sub.2.C.sub.2 H.sub.2 O.sub.4 :                 Found:          62.35% C  5.78% H  7.13% N                                    ______________________________________                                    

EXAMPLE 193-[3-[4-[4-[bis(4-fluorophenyl)butyl]]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazoledioxalate

To 75 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (4.1 g),1-[4,4-bis-(4-fluorophenyl)butyl]piperazine (4.0 g), milled K₂ CO₃ (10g) and KI (0.01 g).

After four hours of stirring at 90° C., the mixture was poured into 300ml of water, stirred for five minutes and then extracted with ethylacetate (3×100 ml). The organic layer was washed with water (2×100 ml)and saturated NaCl solution (1×100 ml) and then dried over anhydrousMgSO₄.

After filtration, the solvent was evaporated, leaving about 9 g of oilwhich was eluted on a silica gel column with ethyl acetate via HPLC. Thedesired fractions were combined and concentrated to about 3.8 g of oilwhich was dissolved in ether and then acidified to pH 1 withetheral-oxalic acid. The resultant precipitate was collected and driedto yield 3.7 g, d @225° C. This material was recrystallized frommethanol/water/ether (50:1:5), to yield 3.0 g of crystals, d @228° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for  59.25% C  5.66% H  5.76% N                                    C.sub.32 H.sub.37 F.sub.2 N.sub.3.2C.sub.2 H.sub.2 O.sub.4 :                  Found:          59.13% C  5.72% H  5.69% N                                    ______________________________________                                    

EXAMPLE 203-[3-[4-[3-[6-fluoro-1,2-benzisoxazol-3-yl]propyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazoledioxalate

To 100 ml of dry DMF were added3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g),6-fluoro-3-[3-(1-piperazinyl)propyl]-1,2-benzisoxazole (5.5 g), milledK₂ CO₃ (10 g) and KI (0.01 g).

After two hours of stirring at 90° C., the mixture was poured into 300ml of water, stirred for five minutes and then extracted withether/ethyl acetate (2×150 ml). The organic layer was washed with water(2×100 ml) and saturated NaCl (1×100 ml) and then dried over anhydrousMgSO₄.

After filtration, the solvents were evaporated, leaving about 12 g ofoil which was eluted on a silica gel column with 5% methanol/DCM. Thedesired fractions were combined and concentrated to 3 g of solid, whichwas redissolved in ether, the pH adjusted to 1 with ethereal-oxalic acidand the resultant precipitate collected and dried to yield 2.5 g, d@214° C. This material was recrystallized from methanol/water/ether(50:1:5) to yield 2.1 g of solid, d @221° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for  54.38% C  5.32% H  8.46% N                                    C.sub.26 H.sub.31 FN.sub.4 O.sub.4.2C.sub.2 H.sub.2 O.sub.4 :                 Found:          54.92% C  5.37% H  8.51% N                                    ______________________________________                                    

EXAMPLE 213-[3-[4-[3-[5,6-dimethoxy-1,2-benzisoxazol-3-yl]propyl]-1-piperazinyl]propyl]-5,6-dimethoxy-1,2-benzisoxazole

To 80 ml of dry DMF were added3-(3-chloroproyl)-5,6-dimethoxy-1,2-benzisoxazole (8.9 g), piperazine(1.3 g), milled K₂ CO₃ (10.0 g) and KI (0.01 g).

After seven hours of stirring at 95° C., the mixture was poured into 500ml of water, stirred for five minutes and then extracted with ethylacetate. The organic layer was washed with water (2X) and saturated NaClsolution and then dried over anhydrous MgSO₄.

After filtration, the solvent was evaporated, leaving about 10 g of oilwhich was purified by elution on a silica gel column with 5%methanol/DCM via HPLC. The desired fractions were collected, combinedand concentrated to 4.7 g of solid, m.p. 164°-165° C. This material wasrecrystallized from isopropyl ether/methanol (1:1) to yield 3.0 g ofsolid, m.p. 166°-7° C.

    ______________________________________                                        ANALYSIS                                                                      ______________________________________                                        Calculated for C.sub.28 H.sub.36 N.sub.4 O.sub.6 :                                             64.10% C 6.92% H  10.68% N                                   Found:           64.54% C 7.00% H  10.75% N                                   ______________________________________                                    

I claim:
 1. A compound having the formula ##STR16## where R₁ is hydrogenor loweralkyl; R₂ is loweralkyl, arylloweralkyl, diarylloweralkyl or--CH₂ CHOHCH₂ OR₅, R₅ being aryl; and R₃ and R₄ are each independentlymethoxy or hydroxy, the term aryl in each occurrence signifying a phenylgroup having 0, 1, 2 or 3 substituents each of which being independentlyhydroxy, nitro, loweralkyl, loweralkoxy, halogen or CF₃ with the provisothat said aryl may not be trinitrophenyl or triiodophenyl, or apharmaceutically acceptable acid addition salt thereof.
 2. The compoundas defined in claim 1, where R₃ and R₄ are both methoxy.
 3. The compoundas defined in claim 2, where R₁ is hydrogen.
 4. The compound as definedin claim 2, where R₁ is methyl.
 5. The compound as defined in claim 1,where R₃ is methoxy and R₄ is hydroxy.
 6. The compound as defined inclaim 5, where R₁ is hydrogen.
 7. The compound as defined in claim 5,where R₁ is methyl.
 8. The compound as defined in claim 1, which isN-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.
 9. Thecompound as defined in claim 1, which isN-[(2,4-dimethoxy)phenylmethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.10. The compound as defined in claim 1, which isN-methyl-N-(phenylmethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.11. The compound as defined in claim 1, which isN-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.
 12. Thecompound as defined in claim 1, which isN-[2-(4-fluorophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.13. The compound as defined in claim 1, which isN-[2-(4-nitrophenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.14. The compound as defined in claim 1, which isN-[2-(3,4-dimethoxyphenyl)ethyl]-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.15. The compound as defined in claim 1, which isN-methyl-N-(2-phenylethyl)-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.16. The compound as defined in claim 1, which isN-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.17. The compound as defined in claim 1, which isN-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-6-hydroxy-5-methoxy-1,2-benzisoxazole-3-propanamine.18. The compound as defined in claim 1, which isN-[3-(diphenyl)propyl]-N-methyl-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine.19. The compound as defined in claim 1, which is N-[(2-hydroxy-3-phenoxy)propyl)propyl]-5,6-dimethoxy-1,2-benzisozazole-3-propanamine.20. A pharmaceutical composition comprising an effective painalleviating or blood pressure reducing amount of a compound as definedin claim 1 and a suitable carrier therefor.